Journal Article

DKFZ-2022-01918

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.

Rafiullah, R. ; Long, A. B. ; Ivanova, A. A. ; Ali, H. ; Berkel, S. ; Mustafa, G. ; Paramasivam, N. ; Schlesner, M.DKFZ* ; Wiemann, S.DKFZ* ; Wade, R. C. ; Bolthauser, E. ; Blum, M. ; Kahn, R. A. ; Caspary, T. ; Rappold, G. A.

2017
Stockton Press Basingstoke

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Please use a persistent id in citations: doi:10.1038/s41431-017-0031-0

Abstract: ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in the ARL13B gene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed by Arl13b hennin (null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B-c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide-exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide-exchange factor and Joubert syndrome.

Keyword(s): ADP-Ribosylation Factors: genetics (MeSH) ; ADP-Ribosylation Factors: metabolism (MeSH) ; Abnormalities, Multiple: diagnosis (MeSH) ; Abnormalities, Multiple: genetics (MeSH) ; Adolescent (MeSH) ; Adult (MeSH) ; Animals (MeSH) ; Cell Line, Tumor (MeSH) ; Cells, Cultured (MeSH) ; Cerebellum: abnormalities (MeSH) ; Child (MeSH) ; Eye Abnormalities: diagnosis (MeSH) ; Eye Abnormalities: genetics (MeSH) ; Female (MeSH) ; Guanosine Triphosphate: metabolism (MeSH) ; Homozygote (MeSH) ; Humans (MeSH) ; Kidney Diseases, Cystic: diagnosis (MeSH) ; Kidney Diseases, Cystic: genetics (MeSH) ; Loss of Function Mutation (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mutation, Missense (MeSH) ; Pedigree (MeSH) ; Retina: abnormalities (MeSH) ; Guanosine Triphosphate ; ADP-Ribosylation Factors ; Arl13b protein, human

Note: DKFZ-ZMBH Alliance

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Contributing Institute(s):

1. Theoretische Bioinformatik (B080)
2. Bewerunge-Hudler (W110)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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